Current estimates suggest that there are 600,000 people in need of treatment for heroin addiction. Unfortunately, there is very little scientific data regarding vulnerability to heroin abuse. This makes it extraordinarily difficult to study the biological substrates responsible for the findings that some people exposed to heroin progress to a compulsive and uncontrolled use of the drug, whereas others use heroin several times, and then stop using it. This question is impossible to experimentally evaluate in humans because of the obvious ethical issues involved in exposing drug-naive people to heroin. If animal models are to be used to understand this phenomenon, then appropriate self-administration methods that allow for a differential sensitivity to be expressed need to be developed. Furthermore, if a procedure that screens for this eventual "vulnerability" was used, then biological studies can be conducted in essentially drug-naive animals, allowing the determination of the mechanisms that produce this differential reaction to drugs of abuse. This proposal is designed to investigate the relationship between sensitivity to the analgesic effects of opioids and various measures of the reinforcing effects of opioids (primarily heroin). Once this relationship is established, animals can be screened for "vulnerability" to drug addiction, and extensive neurobiological and biochemical analyses can be conducted in drug-naive animals. In particular, the following questions will be answered over the course of this award: 1. What is the relationship between sensitivity to the analgesic effects and the reinforcing effects of opioids? 2. What are the differences in the localization, characteristics, or coupling efficiency of the opioid system across subgroups (i.e. "vulnerable" or "resistant") of animals? 3. What are the differences in the expression of various genetic markers and proteins in the brain pathways relevant to opioid reinforcement across these subgroups of animals? This series of experiments will provide extensive training for the candidate in the neurobiology and biochemistry of drug abuse, to complement the behavioral background already established. In the end, this research will identify neurobiological, biochemical and genetic determinants of susceptibility to heroin use. An improved understanding of the individual risk of drug addiction will lead to the development of better prevention and treatment strategies.